New Drug Watch: A Validation of the ‘Twincretin’ Approach to Type 2 Diabetes

The diabetes market is crowded but no one has nailed it yet — here’s why Eli Lilly’s new drug performs better than the competition.

The most buzzed-about drug of Q2 2022 wasn’t a cell and gene therapy, mRNA platform, or CAR-T treatment. Instead of a rare disease being targeted — which has become the standard for attention-grabbing new drugs over the last five years — a breakthrough emerged for a very familiar condition. On May 13, Eli Lilly launched MounjaroTM (tirzepatide), an injectable therapy for adults with type 2 diabetes.1

Addressing a Widespread Disease

Type 2 diabetes is one of the most common diseases in the United States, affecting 10.5% of the population, or 34.2 million people.2 The disease is chronic, progressive, and characterized by the inability to produce or use insulin normally, resulting in high levels of blood glucose, which leads to a constellation of symptoms and susceptibility to other diseases.

Diabetes impacts patients of all ages and poses a profound burden on patients themselves, their caregivers, and the nation. According to the Centers for Disease Control and Prevention (CDC), the total direct and indirect estimated costs of diagnosed diabetes in the United States in 2017 was $327 billion. This number has continued to grow annually — the total direct estimated costs of diagnosed diabetes increased from $188 billion in 2012 to $237 billion in 2017 — while the total indirect costs increased from $73 billion to $90 billion over the same period. Between 2012 and 2017, excess medical costs per person associated with diabetes increased from $8,417 to $9,601.2

Not only is diabetes expensive, but type 2 patients require ongoing treatment. Those diagnosed with this condition must constantly monitor their blood sugar and glucose intake to stay healthy. Insulin injections are the most common way to manage the disease, as is the use of an insulin pump, frequent blood sugar checks, and carbohydrate counting.3

Standard diabetes drugs target and stimulate the pancreas to ensure that more insulin is produced and released. Alternatively, the production and release of glucose from the liver is inhibited, or stomach enzymes that break down carbohydrates are blocked.3

If a diabetic patient’s blood glucose levels go unregulated, there are often severe health consequences, from limb amputation to seizure and even death. Clearly, a drug that could fill this significant gap in treatment and alleviate pressure on patients would have tremendous benefits. Considering the seriousness of the condition as well as its ubiquity, Mounjaro initially received a priority review designation by the FDA before being fully approved. Patrick Archdeacon, M.D., Associate Director of the Division of Diabetes, Lipid Disorders, and Obesity in the agency’s Center for Drug Evaluation and Research, noted, “Given the challenges many patients experience in achieving their target blood sugar goals, today’s approval of Mounjaro is an important advance in the treatment of type 2 diabetes.”1

A New Approach

Unlike currently available therapies, Mounjaro leads to improved blood sugar levels by directly targeting the hormones involved in controlling glucose — glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). A first-in-class medicine, the drug activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control. Unlike insulin, which must be injected at least twice a day, with many patients requiring 3–4 shots or more, Mounjaro is administered by injection under the skin just once weekly. Dosing can be adjusted on the basis of a patient’s individual blood sugar goals.1

Mounjaro can be taken in conjunction with other diabetes medicines or as a stand-alone therapy. Lilly evaluated three different dosages of the therapy (5, 10, and 15 mg) in five clinical trials, where it was tested compared to placebo, a GLP-1 receptor agonist (semaglutide), and two long-acting insulin analogs. For best results, Mounjaro should be administered in a treatment plan along with a change in diet and adding exercise into a routine.1

Patients who were assigned the highest dose of Mounjaro (15 mg) lowered their blood glucose by 1.6% more than those given a placebo. The drug performed slightly better as a stand-alone therapy, as it lowered the trial group’s HbA1c (which measures blood sugar over three months) 1.5% more than a placebo when used in combination with long-acting insulin.1

Aside from being efficacious in its own right, Mounjaro performs more effectively than other therapies on the market. When tested against semaglutide, insulin degludec, and insulin glargine, it lowered patients' HbA1c by 0.5%, 0.9%, and 1.0%, respectively.1

However, perhaps the most significant therapeutic affect was not its impact on blood glucose but on weight loss. According to the FDA, participants lost 15 pounds without insulin and 23 pounds with insulin when taking the highest dose of Mounjaro. The average weight loss with the maximum recommended dose of Mounjaro was 12 pounds more than with semaglutide and 29 pounds more than with insulin degludec. The patients that took insulin without Mounjaro actually tended to gain weight during the study.1

Though it is unknown if Mounjaro is linked to tumors, including medullary thyroid cancer in humans, this does occur in rats. Other reported side effects include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain.1

How Mounjaro Works

As the first “twincretin,” Mounjaro combines the synergistic benefits of controlling glucose metabolism and weight loss through the incretin effect. The incretin effect happens when gut hormone signaling, including through the GLP-1 and GIP receptors, stimulates insulin secretion in response to carbohydrate absorption in the gut.4 These receptors are activated on pancreatic β cells, which enhances the insulinotropic response. This reaction depends on glucose and triggers a proportional response to dispose of the absorbed carbohydrate and lipid load. Oral glucose leads to a higher insulin response than glucose administered intravenously.5

Perhaps unsurprisingly, this effect is impaired in type 2 diabetes sufferers. Though many diabetic treatments revolve around GLP-1–based therapies, GIP’s role is not as well studied.5 However, it’s likely to make a difference, especially based on Mounjaro’s trial results — functioning similarly to gastric bypass surgery on overall health for obese individuals.

GIP may also play an important role in long-term lipid storage and the healthy expansion of white adipose tissue (WAT). This reduces the chance of lipid spillover and fat accumulation in liver, skeletal muscle, cardiac, and pancreatic tissues. In type 2 diabetes, WAT is dysregulated. Its storage capacity is exceeded, which interrupts the ability to buffer lipids appropriately — this leads to reduced insulin-mediated suppression of free fatty acid (FFA) release, lowered adipose tissue perfusion (blood flow), and impaired recruitment of lipoprotein lipase (LPL).5 GIP contributes to lipid disposal and enhances triacylglycerols (TAG), which store and transport energy.5,6 Though there are additional benefits and roles of GIP, it is notably a potent insulin-sensitizer in adipocytes (cells that store fat) and is capable of enhancing glucose uptake. It also has a key role in the CNS, as it may provide further metabolic benefits by reducing energy consumption, especially in combination with GLP-1.5

Though previous research has focused only on the GLP-1, targeting both the GIP and GLP-1 receptors is more efficacious. Eli Lilly’s findings are very promising, and it will be interesting to see how Mounjaro’ addresses the unmet need in diabetes over the long term. Needless to say, the market has taken notice — after releasing news of the drug’s performance, the company’s stock jumped 16 points. Mounjaro could be a game-changer, not only for Lilly if it reaches blockbuster status but for the millions of patients across the country who are currently struggling to manage their weight and blood glucose levels and are burdened by multiple injections per day.


1. FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes. U.S. Food and Drug Administration. 13 May 2022.
2. National Diabetes Statistics Report 2022. Centers for Disease Control and Prevention. 2022.
3. “Diabetes” Mayo Clinic. 30 Oct. 2022.
4. Dungan, Kathleen M.2021 Top Story in Diabetes: ‘Twincretin’ Maximizes Glucose Control and Weight Loss.Diabetes. 8 Dec. 2021.
5. Samms, Ricardo J., Matthew P. Coghlan, and Kyle W. Sloop.How May GIP Enhance the Therapeutic Efficacy of GLP-1?Trends in Endocrinology & Metabolism. 17 Mar. 2020.
6. Pan, Xiaoyue and M. Mahmood Hussain.Gut triglyceride production.Biochim. Biophys. Acta. 1821: 727–735 (2012).

David Alvaro, Ph.D.

David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.